Clostridium perfringens gas gangrene is the most fulminant necrotizing infection affecting humans. In victims of traumatic injury, the infection can become well established in as little as 6-8 hours and the destruction of adjacent healthy muscle can progress several inches per hour despite appropriate antibiotic coverage. Despite modern medical advances and intensive care regimens, radical amputation is often required and mortality remains between 40-70%. The rapid tissue destruction characteristic of clostridial myonecrosis has been attributed, in part, to the absence of a tissue inflammatory response with concomitant vascular leukostasis. We have previously shown that, in vivo, the clostridial phospholipase C (PLC) stimulates the formation of large intra intravascular aggregates of platelets and granulocytes and that formation of these heterotypic complexes is the result of PLC-induced activation of the platelet fibrinogen receptor, gpIIbIIIa. We hypothesize that formation of these complexes prevents normal granulocyte diapedesis and enhances respiratory burst activity of hyperadherent leukocytes, resulting in vascular leukostasis and injury with concomitant ischemic tissue necrosis. Specifically, this proposal will investigate the effects of PLC-stimulated platelets on neutrophil chemotaxis, transendothelial cell migration (adherence and diapedesis), and respiratory burst activity in vitro, and will determine the role of PLC-induced gpIIbIIIa activation in these events. Given the increasing antibiotic resistance among human pathogens, results of this work will provide important new information for the development of a host response-based immunologic strategy to restore the tissue inflammatory response, prevent vascular occlusion and injury, maintain tissue viability, and therefore provide a more modern treatment alternative to radical amputation for patients with this devastating infection.